The term “HAART” (Highly Active Anti-Retroviral Therapy) summarizes a series of methods of treatment, in connection with which anti-retroviral chemotherapeutic substances, specifically inhibiting substances of Reverse Transcriptase (RT) and inhibiting substances of HIV protease are administered in combination to combat AIDS. Typical treatment regimens employ two nucleoside analogue RT inhibitors (NRTI's) and an HIV protease inhibitor or a non-nucleoside analogue RT inhibitor. After bone marrow suppression and the accompanying negative effects of some reverse transcriptase inhibitors on the differential blood count and the immune defense were established as side effects, in part along with neuropathies and myopathies (also of the heart muscle), further side effects became evident with the new forms of therapy. One of them is the so-called lipodystrophy. This term covers a series of symptoms and side effects. While high cholesterol and triglyceride levels are often found with protease inhibitors, further side effects have been observed with the so-called nucleoside analogue, reverse-transcriptase inhibitors (NRTI's). Particularly noticeable are the physical changes, such as the disappearance of subcutaneous fatty tissue in the face, which can lead to shrunken cheeks and sunken eye sockets. The subcutaneous fatty tissue can also be reduced in other parts of the body (e.g., the extremities). In part simultaneously with this, but also in isolation, an abnormal increase in fatty tissue may occur (e.g., in the breasts of the woman and man, intra-abdominally, and in the neck and on the back of the neck). In particular, the latter symptoms are a burden for the patients, who suffer under the fact that, as a result of the therapy, people can “see the disease.” Possible consequences of the changes in fat are, among other things, changes in the metabolism in other metabolic system areas, e.g., in the glycohomeostasis through resistance to insulin, and changes in the fat metabolism, and with that, e.g., the composition of the blood lipids. All of these changes are comprised in the term lipodystrophy. A further effect, especially of the NRTI's, consists in damage to the liver, especially in the direction of an increase in fat (micro- or macro-vesicular steatosis, steato-hepatitis, up to and including liver failure). In addition, numerous other syndromes appear, such as changes in spermatogenesis (reduced sperm count, reduced sperm quality, specifically reduced sperm motility), a surge in cases of pancreatitis and a syndrome of osteopenia, which can be associated with an increase in the lactate level. Further, disorders of the kidney tubuli have been observed, e.g., reduced phosphate resorption. Finally, numerous HIV patients taking NRTI in long-term anti-retroviral therapy manifest diminished aerobic capacity on the basis of a diminished oxygen intake. All of the above-named changes seem to be long-term side effects of the different active agents used in the context of HAART, in connection with which most of the above-named problems seem to be those of long-term therapy with NRTI's.
Because HAART makes available very effective therapies, however, there is a great need for forms of treatment of this nature. For this reason, options are urgently needed to limit, reduce, or eliminate these new side effects, specifically lipodystrophy, disorders of spermatogenesis and the sperm function, the imbalance in the mineral salt content of the bones (above and below referred to as osteopenia), the more frequent appearance of pancreatitis, diminished aerobic capacity and/or disorders of the kidney functions, as well as myopathies and/or weakening of the cells of the immune system. Up to this time, primarily adjustments in nutrition and prophylaxis against side effects were used as therapy, in addition to the intake of vitamins and minerals and the intake of unsaturated fatty acids, carnitine and the glutathion precursor N-acetylcysteine, without a noticeable effect.
A further side effect of NRTI's is hyperlacticemia, which can lead to lactic acidosis, with symptomatic and in part life-threatening acute forms. Discontinuing the NRTI's only leads slowly to recovery, and the use of cofactors or antioxidants such as ubiquinone, antioxidants, carnitine, riboflavin, and thiamin, has only a limited effect.
The treatment of all the side effects named has, all in all, been rather unsatisfactory up to now the temporary discontinuance of NRTI's and/or other inhibitors of the biosynthesis of nucleic acids or its precursors, because of the danger of the development of resistance and progression of HIV-associated immune deficiency, is for the most part undesirable, as is a change in medication.
Patients infected with other viruses, e.g., the hepatitis B virus, the hepatitis C virus, the CMV virus, other herpes viruses (e.g., the varizella-zoster virus, and herpes simplex viruses, the Epstein-Barr virus, HHV type 6 and HHV type 8) and by the JC-virus, can also be treated with nucleoside analogues (e.g., with Acyclovir, Valacyclovir, Famaciclovir, Brivudin, Ribavirin, Ganciclovir, Tenofovir, Cidofovir and Adefovir) and suffer the same above-mentioned side effects. Conversely, the simultaneous therapy with the nucleoside analogues against above-mentioned viruses can intensify the long-term side effects of the above-mentioned anti-HIV drugs. Individual side effects in the use of these antiviral substances can be significantly more evident than those with NRTI's, e.g., manifestation of the disorder of the kidney known as Fanconi syndrome.
For this reason, there is an urgent need to combat the above-named undesirable effects of these medications, specifically lipodystrophy, changes in the sperm and/or osteopenia, in addition, pancreatitis, disorder of the kidney, diminished aerobic endurance, liver damage and/or lactic acidosis, as well as to combat myopathies and to reactivate existing immune cells.
In U.S. Pat. No. 5,968,914, the treatment of bone marrow suppression induced by AZT and the accompanying anemia, as well as ddC-induced peripheral neuropathy, ulcers of the mouth, reduced number of thrombocytes, and the side effects on the muscles, peripheral nervous system, immune system, and gastro-intestinal tract caused by anti-viral therapy through the administration of acylated non-methylated pyridine nucleoside, is described. WO 00/11952 describes, among other things, the treatment of the side effects of cancer chemotherapy, such as peripheral neuropathies, kidney ailments and fatigue caused by the administration of pyrimidine nucleotide precursors.